Murine norovirus (MNV) is emerging as a potential pathogen in mice and its prevalence in research facilities around the world is causing concern among investigators using mice. Initially, the virus was reported to cause morbidity and mortality only in immunocompromised mice while it did not cause any clinical signs of overt diseases in immunocompetent mice. However, we found that MNV infection can induce subtle changes in immune responses even in wild type mice and that MNV infection was associated with an increase in aortic sinus lesion size in Ldlr-/- mice, a commonly used mouse model for atherosclerosis research. We observed that larger aortic sinus lesions in MNV infected mice were associated with increased numbers of macrophages. Others have reported that MNV has a tropism toward macrophages as well as dendritic cells. Our preliminary studies have also found that MNV infection alters the production of several inflammatory cytokines in bone marrow derived macrophages. Thus, we hypothesize that MNV is a potential intercurrent variable in atherosclerosis research partly by influencing macrophage recruitment, cytokine/chemokine profile, and or accumulation in atherosclerotic lesions. To test our hypothesis, we will first determine whether MNV infection exacerbates atherosclerosis in an additional mouse model, ApoE-/- mice. Next, we will investigate whether early exposure (before onset of atherosclerosis) to MNV alters disease phenotype in two commonly used mouse models, Ldlr-/- and ApoE-/-. Finally we will determine how MNV might alter the disease outcome by examining changes in macrophages, important innate immune cells involved in disease initiation and progression. Proposed studies in this application will provide information that can be used to determine whether time and effort should be invested in elimination of MNV from mouse research facilities. Thus, our application is in line with the objective of the current RFA to support investigation of the impact of murine norovirus infection on immune responses.